Xanthin derivative and process of making same.



UNITED STATES PATENT OFFICE.

FRITZ ACH, on MANNHEIM, GERMANY, ASSIGNOR TO 0. F. BOEHRINGER soEnNE, or WALDl-IOF, GERMANY.

XANTHIN DERIVATIVE AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 631,757,

dated August 22, 1899.

- Application filed February 18, 1898- Serial No. 670,847- (SpecimensJ To all whom it may concern.-

Be it known that I, FRITZ ACE, a citizen of the Empire of Germany, residing at Mannheim, in the Empire of Germany, have invented certain new and useful Improvements in the Art of Preparing Xanthins; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This invention relates to the manufacture of xanthins and their derivatives, and more particularly the preparation of this class of bodies from alkylized uric acids.

In order to define more exactly the ground which this invention occupies in the art, it is to be stated that a method has heretofore been found of obtaining the halogen derivatives of alkylized xanthins by the action of phosphorus-chlorid thereon, the xanthins, themselves, being then obtained by reducing the halogen derivatives. This method has been set forth in United States Patents to Emil Fischer, Nos. 569,489 and 569,490, dated October 13, 1896. According to these patents such conversion was, however, only possible for such alkyluric acids as contained two alkyl groups in the alloxan ring and whose structure would be represented by the general formula:

men oo 2 oo 5 o 1 1n oo s amt (J-rune roxanthins has hitherto been impossible. My investigations and experiments in this field have resulted in the discovery that all uric acids which have not been completely alkylized may be converted into the corresponding chloro-xanthins provided no alkyl group has been bound to the nitrogen atom in the posi tion 9. In the latter case only chloro-purins would result. This discovery demonstrates that, contrary to the opinion hitherto entertained, it.is immaterial for the preparation of xanthins from uric acids whether the nitro gen atoms 1 and 3-71. 6., those in the alloxan ring-are alkylized or not. All that is material in this respect is that the nitrogen atom 9 be not alkylized. I have, moreover, ascer tained as a result of my investigations that it is necessary to act upon the alkylized uric acid with phosphorus-oxy-chlorid alone in order to proceed to xanthins and that this result cannot be attained if the phosphorusoxy-chlorid acts on the alkyl-uric acid in conjunction with phosphorus-penta-chlorid, for example. A comparison of the entirely and essentially difierent results obtained by acting on the same alkyl-uric acid first with phosphorus-oxy-chlorid together with phosphoruspenta-chlorid, according to the methods heretofore known, and then with phosphorus-oxychlorid alone, will serve admirably to emphasize the essence of the present invention. Thus if, for example, 7 -monomethyl-uric acid is submitted to the joint action of phosphorus-oxy-chlorid and phosphorus-penta-chlorid the oxygen bound to the alloxan ring alone is replaced by chlorin, the resultant compound being 7 -methyl-8-oxy-2-6-dichloropurin HN-CO N=C.Cl

If, however, phosphorus-oxy-chlorid alone is caused to react on 7-monomethyl-uric acid, chlorin is substituted for the oxygen occupying the position 8, whereby the xanthinderivative 7-methyl-2-6-dioxy-S-chloropurin' or 7-methyl-chloro-xanthin is obtained.

oo o u.on, oo o-nlon,

Again, it 3-7edimethyl-uric acid be treated with phosphorus-oxy-chlorid together with phosphorus-penta-chlorid there is formed 3-7- dimethyl-2-8-dioxy-6-ch1oropurin, as shown in Berichie de r Deaischen Chemz'schen Gesellschaft, Vol. 28, page 2480, and Vol. 30, page 554:

. HN- CO oo o N.ou,- oo c-Non, r l W I-IN-CO HNCO N:C.Cl

I have found that the same result is obtained with other alkyl-uric acids, and, in general, my invention shows that the use of phoswhile the treatment of such uric acids with both phosphoros-penta-chlorid and the oxychlorid would result in chloropurins, which are not xanthin derivatives.

products, apparently containing phosphorus and chlorin, are at first formed when phosphorus-oxy-chl'orid reacts upon alkylized'uric acids, these intermediate bodies being subsequently changed into chloroxanthins by treatment with suitable means,'such as alcohol or water, while phosphoric acid and hydrochloric acid are'spli-t elf.

The chloroxanthins obtained under my invention are converted into higher alkylized' products by employing the alkylizing methods which are in use in connection with the uric acid and xanthin series. Thus, for example, chloro-theobromin may be obtained from S-methyl-chloroxanthin on further methylation, the chloro-theobromin being in turn readily susceptible of conversion into chloro-caffein by the same methods.

, dilute sulfuric acid.

The chloro-xanthins are converted into the corresponding xanthins by reducing methods.

It is to be noted that under my invention other alkyl radicals than the methyl group may be introduced into the Xant-hin-molecule. Thus the 3-methyl-ehloro-xanthin is readily converted into 3-m-ethyl-1-7-diethyl-chloro- Xanthin by introducing the ethyl radical into the former.

For the purposes of my invention it is unimportant whether the lower chloro-Xanthins are first alkylized and then reduced, or vice versa. In both ways I may proceed to the higher alkylized Xantliins, such as caifein.

My invention, whose object is to obtain xan thins from uric acids,accordingly, broadly considered, consists in submitting alkalized uric acids, which, however, have no alkyl group at the position 9 to the action of phosphorus oXy-chlorid. The said invention, moreover, consists in the subsequent reduction and alkalization of the resultant compounds, and, moreover, in the special prod nets and subprocesses, all as will be hereinafter specified, and pointed outin the claims hereunto annexed.

I will now proceed to fully disclose my invention for those skilled in the art by giving in detail a number of examples embodying what I consider the best manner of carrying said invention into effect.

I. Preparation of Halogen Derivatives of Allcalz'zed Xantht'ns from the Corresponding U'ric Acids.

1. Preparation of S-methyZ-chloro-xanthm from -methyZ-aric acid.-One part of anhydrous 3-methyl-uric acid is added to five parts, by volume, of phosphorus-oxy-chlorid and heated under pressure-e. g., in a digester to from 130 to 140.centigrade, and main .tained at this temperature for from three to four hours, the mass being steadily agitated. The resulting clear reddish-brown solution is then evaporated in cacao for the purpose of completely removing the phosphorus-oxychlorid. The brownish residue, which has a tough varnish-like consistency, is thereupon Accordlng to my observations, intermediate brought into solution by boiling the same with about five times its quantity of alcohol or water. The alcoholic solution, which at first is clear, but soon becomes turbid on account of the precipitation of granular crystalline methyl-chloro-xanthin, is boiled for from two to three hours-in a reflux-condenser and then allowed to cool. Upon then filterin g the methyl-chloro-xanthin remains on the filter as a yellow granular crystalline mass. The filtrate is then evaporated, whereby a second crystallization ensues, resulting in a further yield of the above productmethylchloro-Xanthin. The crude product so obtained is brought into solution with dilute alkali, such as two per cent. potash-lye, treated with animal charcoal or other deco1- orizing agent, and finally precipitated with On cooling, the new compound is obtained in the form of yellowhued coarse crystals, from whose analysis are obtained figures which show the formula of this compound to be C H N O Cl+H O. Its structural formula is found to be:

HN-CO such formula being established by the fact of the ready conversion of this compound into chloro-cafiein. (See under H la.) I therefore designate this new compound as 3-methylchloro-Xanthin or S-methyl-S-chloro-xanthin. The tenaciously-adhering yellow tint, which is very difficult of removal, has no infiuence on the percentage composition of the product.

Absolute decoloration of the methyl-chloro- Xanthin maybe attained by thoroughlyboiling it with a large quantity (thirty parts to one part of the methyl-chloro-Xanthin) of acetone. The xanthin is thereby gradually brought into solution, while the adhering coloring matter remains undissolved. Upon cooling after such solution is effected the methyl-chloro-xanthin crystallizes in anhydrous fine colorless shining foliated crystals or scales.

3-methyl-chloro-xanthin is soluble in about two hundred and fifty parts boiling water, and on cooling the solution slowly the same crystallizes therefrom in coarse needles,which under the microscope are found to be elongated fiat prisms and which contain one molecule of water of crystallization. This water of crystyllization escapes on protracted heating at 120 centigrade. It is difficult of solution in boiling alcohol, in acetone, aceticether, benzene, or chloroform, readily soluble in dilute alkalies, in ammonia and soda, or potash solutions. It is equally soluble in concentrated sulfuric acid and fuming hydrochloric acid. From a solution in the latter the original product is precipitated by water on standing for some time. Heated with chlorin water or with dilute nitic acid it gives a strong murexid reaction. An ammoniacal solution of the same added to an ammoniacal silver solution yields a gelatinous silver-salt which remains unchanged on boiling.

3 methyl chloroxanthin has no meltingpoint; but on being rapidly heated it begins to turn yellow at 320 centigrade, and at about 345 centigrade it decomposes with efiervescence.

2. Preparation of V-Wwth L-Q-d-d-ioxy-S- chloropm'in or chloro-heteroxanthin from '7- monomethyZ-uric acid-.One part, by weight, of dried and finely-powdered 7-mono-methyluric acid is'added to ten parts, by volume, of

Vphosphorus-oxy-chlorid and boiled for from twenty-four to thirty hours in a reflux-condenser. This treament results in the solution of methyl-uric acid, a clear slightly-colored liquor being formed. This liquor is evaporated in vacuo, and the tough, Varnish-like residue is taken up with warm alcohol. After boiling such solution a short time the chloro-heteroxanthin is thrown out in the form of a colorless crystalline mass, which is separated by filtration. This product is not quite pure, but is contaminated with some unchanged methyl-uric acid, which may be removed by boiling with m uch acetone, which dissolves the chloro-heteroxanthin but not the methyl-uric acid. The acetone solution is then evaporated, and the resulting crystalline residue is taken up with dilute ammonia, treated with decolorizin g carbon, and precipitated with dilute sulfuric acid. The 7- methyl-chloroxanthin or chloro-heteroxanthin is thereby obtained in the form of colorless short prismatic crystals which give figures corresponding to the formula C H N 0 01. Its structural formula is HNCO 0O (J-NCH 001 HN-O-N asis shown by its conversion into chloro-caffein. (Sec II 11).)

The chloro-heteroxanthin or 7 -niethyl-2-6- dioxy-S-chloro-purin is formed about according to the equation:

That this new product is a xanthin derivative is also corroborated by the fact that it gives the murexid test with chlorin-water or dilute nitric acid. From boiling water, in which it is moderately soluble, it crystallizes in short needles which are frequently aggregated in bunches. It is soluble with difficulty in alcohol and acetone and with very great difficulty in benzene or chloroform. It is readily taken up by dilute alkalies, ainmonia, and soda or potash (carbonates) solutions. An ammoniacal solution of the same, added to an am moniacal silver solution, gives rise to a colorless silver-salt consisting of fine needles, which salt remains unchanged on boiling.

Ohloro-heteroxanthin has-no melting-point but on-being heated rapidly it becomes yellow at about 300 centigrade and is decomposed at about 340 centigrade, the decomposition being attended by dark-brown coloration and duced to the finest possible powder is added to five parts, by volume, of phosphorus-oxychlorid and the whole boiled with reflux until a clear solution is formed. This requires about twenty hours. From the resulting liquid, which is slightly colored, the unchanged hol.

phosphorus-oXy-chlorid is distilled off in vacuo and the residue is dissolved with alco- The solution is then boiled. After a short time the chloro-theobromin which'has been formed begins to crystallize out of the solution. The reaction takes place about according to the equation:

HN-CO OILN- C-NH HN-CO The crystals are then separated by filtration and dissolved in dilute alkali and treated with carbon for decoloration, whereupon the chloro-theobromin is thrown outby dilute sulfuric acid. The colorless product so obtained.

has the composition indicated by the formula G H N,O Gl and the structure,

I-IN-CO oc C-N.CH3

melts at about 292 to 293 centigrade to a slightly-colored liquid, which soon congeals to a crystalline mass on cooling. It dissolves in about two hundred and fifty parts of water on boiling. From such aqueous solution it is thrown out in theform of colorless vitreous shining short prisms on'cooling slowly and in the'form of fine needles aggregated in bunches on cooling rapidly. It is only difficultly soluble. in boiling alcohol. On the other hand it is readily soluble in'dilute alkalies and dilute warm ammonia. From a solution of the samein soda-lye its sodiumsalt is rapidly thrownout in the form of fine acicular crystals by concentrated soda-lye. If an ammoniacal solution of the same be added to an ammoniacal silver solution and the ammonia be removed by boiling, a gelatinous colorless silver-salt of the chloro-theobromin is thrown out.

II. Conversion of the Above Halogen Derivatines-into Higher AZkyZ-zlzed Products.

1. PreparationofchZoro-ccqfiein. (a) From 3-meihyl-ohZoro-manthin.One part, by Weight, of 3-methyl-chloro-Xanthin, which has been described herein'above, is brought into solution with five and four-tenth parts,

by volume, of double-normal potash-lye (potassium-hydrate) and equal parts of water, and after one and one-half parts, by weight, of 'methyl-iodid have'been added thereto the whole is heated to 90 Centigrade in thepressure-tube and maintained at this temperatu re for from two to threehours, the mass being constantly agitated. The same is then allowed to cool, when the greater portion of the chloro-caffein which hasbeen formed is thrown out in the form of fine needles. The balance of the chloro-caffein is obtained by extraction from the lyes, which have previously been rendered slightly alkaline by a suitable solvent, such as chloroform, for example. The formation of chloro-caifein takes place according the equation:

'HN-oo The actual amount of chloro-caffein obtained corresponds to the theoretical yield. It is fully purified on once recrystallizing from water and has all of the characteristic properties found for chlorocaft'ein by Emil Fischer, (Annalen, Vol. 215, page 263.)

(1).) From 7-methyl-chloroxanthtn.Three parts, by weight, of V-methyl-chlorozanthin or chloro-heteroxanthin,Which has been hereinbefore described, are dissolved in eighteen parts, by volume, double-normal caustic-potash lye (potassium-hydrate) and thirty-six portion parts, by volume, of water, and after adding thereto five parts, by weight, of methyl-iodid the same is heated to 90 centigrade in the pressure-tube, this temperature being maintained for two and one-half hours and the; massbeing constantly agitated. After allowing the same to cool the resultant chloro-caffein will be found to exist in the tube in the f form of a paste or pulp. It is isolated as set I forth under (a).

The conversion of chloro-heteroxanthin or 7-methyl-chloroxanthin into chloro-caffein takes place according to the equation: I-IN-CO thins, such as chloro-t-heobromin, which is 3-7 j dimethyl-Q-G-dioxy- S- chloropn rin or 3-7-dimethyl-S-chlorozanthin, will again result in the trimethyl-chloroxanthin or chlorocaffein.

If two parts, by weight, of the chloro-theobromin which has been described under head i I 3 be dissolved in seven volumes of doublenormal potash-lye (potassium-hydrate) and seven volumes of Water and heated to 90 centigrade under pressure, together with one and one-half parts of methyl-iodid, this temperature being maintained for three hours and the liquid constantly agitated, the formation of chlorocatfein will take place. The greater of the same is thrown out in the form of fine acicnlar crystals after cooling, while the remainder is obtained by extraction with a suitable vehicle, such as chloroform. The following equation explains the reaction which takes place:

IIN- CO 6o cum c N with twenty parts, by volume,

Here, again, the theoretical and practical yield are identical.

2. Preparation of chlorotheobrom'in from 3- methyZ-chloroxanthin.-Six parts, by weight, of S-methyl-chloroxanthin are dissolved in eighteen parts, by volume, of double-normal potash-lye (potassium-hydrate solution) and v thirty parts, by volume, of water. There are then added to the solution seven and two- 1 tenths parts of methyl-sulfate of potassium,

and the whole is then heated to from 140 to 150 centigrade under pressure--e. g., in a digester-t his temperature being maintained for from four to five hours and the mass constantlyagitated. Upon cooling the chlorotheobromin 3-7-dimethyl-S-chloroxanthin is separated out of the solution in the form of coarse yellowish-brown granular crystals. It

is purified by redissolving and crystallizing out of alkalies, such as potash-lye, and possesses all of the characteristic properties, as well as the melting-point, of the chlorotheobromin described under I 3. The reaction which results in its formation proceeds according to the equation:

3. Preparation of 3-011ethyZ-1-7-diethyZ-2-6- dioxy-S-chloroparin from fl-methyl-chloromaniht'n.Four parts, by weight, of 3-methylchloroxanthin are dissolved in twenty-three parts, by volume, of double-normal potashlye (potassium-hydrate solution) and diluted of alcohol. Six and one-half parts, by Weight, of ethyliodid are then added, and the Whole is boiled for from three to four hours in a reflux-condenser. The mass is then allowed to cool, when it solidifies in the form of a pulp or fine felted needles. These are then separated by filtration, redissolved in boiling water, and recrystallized therefrom. crystals so obtained have the composition indicated by the formula C ll Np Ol or, struc turally expressed,

0O O-N.C H

001 i ll OLI .NCN The reaction to which the formation of the The fine acicnlar the equation:

This new compound, with chlorin-water, gives a strong murexid reaction. Its melting-point is 136 centigrade. It is moderately soluble in. boiling and difficultly soluble in It dissolves readily in hot alcohol and in cold acetone or chloroform. It is also readily soluble in fuming hydrochloric acid, being precipitated from such solution by water. It will be noted that its structure closely resembles that of chloro-caflein, the only difference being that in lieu of the methyl groups in the positions 1 and 7 in the latter compound it has substituted ethyl groups. crnN-co o,i-I .N-oo

oc c-Non oo o nc n I 'l ool I I ooi i CH3.NON on n- -n Chloro-catfein or 1-3-7-t1'imethyl-Schloro-xan thin 01'1-3- '2-trimethyl-8-chloro-2-6-dioxypurin.

1-7-diethyl-3-methyl-8-chloro xan thin or 3-methyl-1-7-diethyl- S-chloro-fi-G-dioxy-purin.

III. Reduction of the Halogen Derivatives 250 the Corresponding Xanihins.

1. Preparation of 3-meihg Z-2=6-diowypu rin or B-meihyZ-acanihtht from 3-77'LGflZ-Zjl-Chl070- manthin.1f one part, by weight, of 3-methylchloro-Xanthin, described under head I, is heated with ten times its weight of fuming hydriodic acid, a gradual solution and reduction of the chloro compound takes place,which -is attended by a liberation of iodin. The heating (at a temperature of from to centigrade) is continued and phosphonium iodid added from time to time until a clear colorless solution is formed. The solution is then evaporated, whereby the iodohydrate of this new base is thrown out in the form of coarse colorless prismatic crystals. After the evaporation has been continued to complete dryness the residue is taken up with water, which causes the iodohydrate to be decomposed and the methyl-xanthin to be isolated in the form of fine colorless needles. The

practical yield corresponds to the theoretical. The base is recrystallized from boiling water and so obtained in the form of fine shining needles. Its formula is C HN O or, structurally:

HN-CO ()0 CNH l H i ll OH .N-CN

The reaction, as a result of which it is ob tained, is expressed in the equation:

nN-oo This new base as a xanthin gives a strong murexid reaction only with chlorin water, while it it is evaporated together with moderately-concentrated nitric acid it yields a slightly-colored residue, which is dissolved in strong potash-lye,'and thus forms a cleardeepyellow solution. It requires from three hundred to three hundred and thirty parts of boiling water for solution, but is readily soluble in dilute alkalies and ammonia and also in concentrated sulfuric orhyd'ro'chloric acid. An ammoniacal solution of the same when added to a solution of nitrate of silver gives rise to a colorless silver salt consisting of fine needles. This silver salt dissolves in a large excess of ammonia on heating and remains ilnchanged on boiling. If a solution of the 3-methyl-xanthin in dilute nitric acid is added to nitrate of silver, a double salt,

consisting of coarse acicular crystals intermeshed in the form of bunches, is thrown out. This double salt is readily soluble in hot water. I

3-methyl-xantl1in has no melting-point. When heated above 360 centigrade, it begins to become yellow, and on raising the temperature above 400 centigrade it is decomposed without melting.

This new bodydiffers from the compound, heteroxanthin, described in Patents Nos. 617,985 and 617,986, dated January 17, 1899, only in the location of the methyl group. While in the latter compound this group is in the position 7, in the present compound it occupies the position 3.

2. Preparation of 7-meihyZ-2-6-clioaiy-parin or heie'roxanihin from 7-methyl-8-chZ0r0-zcanthin-.-If one part, by weight, 0f'7 -methylchloro-Xanthin, (described under I be heated on the water-bath,together with eight times its weight of fuming hydriodic acid of the specific gravity 1.96, phosphonium-iodid being added from time to time to the mixture, a clear colorless solution is soon formed, whereby the end of the reaction is indicated. The reaction proceeds according to the equation:

' The resultingliquid is evaporated to dryness,

and the residue is repeatedly dissolved in water and evaporated to completely remove the hydriodic acid. The crystalline residue is then suspended in about twenty parts of hot water and soda-lye (sodiumhydrate) is added until complete solution is effected, when it is allowed to cool. On cooling, the characteristic difficultly-soluble sodium salt of heteroxauthin is thrown out in the form of coarse colorless crystals. This reaction is expressed in the equation:

llN-CO O0 UNCII.,+H.,O.

CII Na.NCN

The heteroxanthin may then be liberated from the sodium salt by dissolving in hot water, su persaturatin g with acetic acid and separating by filtration. The heteroxanthin so obtained possesses all the characteristic properties enumerated in Emil Fischers patent, No. (318,0i5, .dated January 17, 1899.

8. Preparation of S-T-dimethyZ-Q-Gdiarypm'in or theob'romin from chloro theobromin-1f one part, by weight, of chlorotheobromin or 3-7 dimethyl-2-6-dioxy-S-chloropnrin, which has been described under head 1 be heated on the water-bath with eight times its weight of funiinghydriodic acid of the specific gravity 1. 96, one-half (about) part of 'phosphoniuni-iodid being added, a colorless clear solution will be obtained after the lapse of from fifteen to twenty minutes. This indicates that the reduction of the chlorotheobromin has been completed. The liquid is then evaporated to complete dryness to eliminate the surplus of hydriodic acid. colorless crystalline residue is then taken up with water, whereby the said residue is first dissolved. After a short time, however, the

The

formation of colorless indistinct crystals ensues. These are redissolved and recrystallized from boiling water, and they possess all the characteristic properties of theobromin. They crystallize in small colorless prisms, melt at about 345 centigrade without decomposition, and when dissolved in nitric acid they unite with nitrate of silver to form the double salt, which forms fine needles. The reducing reaction whereby the theobromin is formed from the chloro-theobromin is elucidated in the equation:

HN-CO oo o-Non, +11

1 l o.c1

onus-04v liN-CO 0o O-NCIL, +HC1.

The theoretical and practical yieldsof'theobromin are identical.

4. Preparation of 3-methyZ-1-7-diethyZ-2-8- (ZL'oxy-pm'in.This new body is obtained by reduction of 3-methyl-l-7-diethyl-2-(3-dioxy- S-chloropurin or S-m ethyl-l-7-diethyl-S-chloro- Xanthin, which has been described under head 11 If one part, by weight, of this chloroxanthin be heated with ten parts, by weight, of fuming hydriodic acid to centigrade, solution is speedily effected. The heating is then continued on a boiling waterbath so long until with the addition of phosphonium-iodid in sufficient quantity to take up the liberated iodin a clear solution is formed. This solution is then evaporated to dryness and the crystalline residue is taken up with water and supersaturated with alkali. Through this treatment the new base separates as a colorless oil, which very soon congeals, forming fine acicular crystals. The base is then extracted with a suitable vehicle, such as chloroform or ether, whereupon the extract is evaporated and the colorless residue recrystallized from benzene. From the benzene solution, to which ligroin is preferably added, the methyl-diethyl-dioxypurin crystallizes in the form of splendidlydeveloped vitreous colorless prisms, whose analysis gives figures which correspond well to the formula O H N O The structural formula of the base is ou-nnoo oo o-noni,

The reducing process is expressed in the' equation:

As a Xanthin this new body with chlorinwater gives a strong lnurexid reaction. It melts at from 127 to 128 centigrade. It is readily soluble in water, alcohol, chloroform, benzene, ether, and concentrated hydrochloric or sulfuric acid. From an aqueous solution this mass is precipitated by concentrated alkaline lyes as a colorless oil which soon solidifies to a crystalline mass.

IV. AZkg Zt'zing Subsequent to Reducing the Halogen Derivatives.

Allcylz'zation of 3-meth z Z-xanthin.In preparing the higher alkylized xanthins from the chloro-Xanthins described under I it is not indispensably necessary to first further alkylize the chloro-xanthins and then to reduce such higher alkylized products; but the order of these stepsmay be equally Well reversed by first reducing the chloro xanthins and then alkylizing the reduced products. My invention therefore, broadly considered, consists in reducing and alkylizing the chloroxanthins irrespective of the .order of these two steps.

1. Preparation of 3 7 dimethyl mcmth'z'n (theobrom'in) from 3-methyZ-ocanihin.Seven parts, by Weight, of 3-methyl-Xanthin are dissolved in twenty-six parts, by volume, of potash-lye (potassium-hydrate solution) of double normal strength, and fifty parts, by volume, of water, and, after adding thereto eight parts, by Weight, of methyl-iodid, heated to centigrade and maintained at this temperature for three hours while constantly agitating the mass. After cooling, the liquid will be found to be filled With a pulpy mass of colorless crystals. The mother-liquor is removed from these crystals by filtration or otherwise, and they are then redissolved in and recrystallized from boiling Water. The colorless crystals so obtained possess all of thecharacteristic properties of natural theobromin. The reaction takes place according to the equation:

HNCO

2. Preparation of 1-3-7-ir2'meth3 Zacmth'm (caflez'rt) from d-methyZ-scanthin.0ne part, by weight, of 3-methyl -Xanthin is dissolved in 6. 8 parts, by volume, of double normal potash-lye (potassium-hydrate solution) and fifteen parts, by volume, of Water and heated to 80 centigrade, together with two parts, by Weight, of methyl-iodid, this temperature being maintained for three hours and the mass constantly agitated. The clear liquid so obtained is highly evaporated and then extracted with chloroform. The fine acicular crystals resulting from this treatment have the melt ing-point 232 centigrade and all of the other properties of calfein. The reaction takes place The yield in cafiein obtained corresponds to the theoretical yield.

It will be seen from areview of the above that my invention, broadly considered, consists in treating an alkyl-u ric acid, having no alkyl in the position 9, with phosphorus-oxychlorid alone, and also in the process of alkylizing such of the chloro-xanthins resulting from such treatment, with or without subsequent reduction of the alkylized chloro-xanthin. It will be observed, moreover, that it is immaterial whether the alkylization precedes or follows the reduction of the chloro- Xanthin, and that alkylization with subsequent reduction is to be considered as an equivalent of red notion of the chloro-xanthin with subsequent alkylization.

Although I have herein described the new compounds, '7-methyl-chloro-Xanthin and 3- paring 7-dimethyl-chloro-xanthin, and the methods of preparing the same and also of reducing and alkylizing them in illustration of my invention, I do not herein claim these new compounds nor the specific methods involved in their preparation, since these form the subjects-matter of and are claimed in my applications, Serial Nos. 670,848 and 678,849, filed concurrently herewith, (Cases K and L.) Nor do I herein claim the new compound, 3- methyl-xanthin (having the methyl group in the position 3) or the specific process of preparing the same, although they have been herein described in illustration of my invention, broadly considered, nor specifically the process of first reducing and then alkylizing the S-methyl-chloro-Xanthin, since all of these are claimed in my application, Serial No. 672,543, filed March 4, 1898. The invention covered in the present application, however, consists in the method broadly of alkylizing and reducing the 3-methyl-chloro-xanthin when the same is considered irrespective of the order of these two steps. Finally I do not herein claim the compound 3-methyl-1- 7-diethyl-2-6-dioxypurin or 3-methyl-1-7-diethyl-xanthin or the specific methods of prethe same, since these form the subject-matter of and are claimed in my application, Serial No. 724,838, filed July 22, 1899.

hat I claim, and desire to secure by Letters Patent of the United States, is-

1. The process in the art of preparing Xanthins which consists in acting upon alkylized uric acids having no alkyl group in the position 9 with phosphorus-oxy-chlorid.

2. In the art of preparing xanthins the process which consists in addingphosphorus-oxychlorid to an alkyl-uric acid having no alkyl group in the position 9 and heating the mixture.

3. In the art of preparing Xanthins the process which consists in adding phosphorus-oxychlorid to an alkyl-uric acid having no alkyl group in the position 9 and heating the mixture, then evaporating the resulting solution to remove surplus of phosphorus-oxy-chlorid, then dissolving the residue after evaporation with alcohol or water and boiling such solution.

4. In the art of preparing Xanthins the process which consists in adding phosphorus-oxychlorid to an alkyl-uric acid having no alkyl group in the position 9, heating the mixture, then evaporating the resulting solution to remove surplus of phosphorus-oxy-chlorid,then dissolving the residue after evaporation with alcohol or water and boiling such solution, then allowing the solution to cool and filtering to evaporate the crystalline alkyl-chloroxanthin from the mother-liquor.

5. The process which consists in treating an alkyl-uric acid, having no alkyl group in the position 9, with phosphorus-oxy-chlorid, and then after isolating the resultant chloro- Xanthin, alkylizing the same.

6. The process which consists in treating an alkyl-uric acid, having no alkyl group in the position 9, with phosphorus-oxy-chlorid and then after isolating the resultant compound, submitting the same to alkylization and reduction.

7. The process which consists in treating 3-methyl uric acid with phosphorus-oxychlorid.

8. The process which consists in heating 3- methyl-uric acid with phosphorus-oxy-chlorid under pressure, then evaporating the resultant clear solution to recover the excess of oXy-chlorid, then boiling the residue in alcohol, then coolingand filtering, all substantially in the proportions and under the conditions set forth.

9. The process which consists in heating 3- methyl-uric acid with phosphorus-oXy-chlorid under pressure, then evaporating the resultant clear solution to recover the excess of oxy-chlorid, then boiling the residuein alcohol, then cooling and filtering, then dissolving the crystalline crude productin alkali to which a decolorizing agent is added, and

precipitating with acid, all substantially in the proportions and under theconditions set forth.

10. Asa new chemical compound, 3-methylchloro-xanthin, which has the formula hereinabove given, is difficult of solution in boiling alcohol, in aceton, acetic ether, benzene or chloroform, but readily soluble in dilute alkalies, in ammonia soda or potash solutions,

soluble in concentrated sulfuric or fuming hydrochloric acid, has no melting-point, but on being rapidly heated, begins to turn yellow at about 320, centigrade, decomposing at about 345, centigrade, with effervescence, and crystallizes from boiling water on cooling in coarse needles, containing one molecule of water of crystallization, which escapes on heating at 120 centigrade.

11. The process which consists in submitting 3-alkyl-chloro-Xanthin to the action of reducing and of alkylizing agents.

12. The process which consists in submitting 3-methyl-ch1oro-Xanthin to the action of reducing and of methylating agents.

13. The process which consists in submitting 3-methyl-chloro-xanthin to the action of a methylating agent.

In testimony whereof I affix my signature 

